We propose to evaluate several hypotheses relating to the incidence and progression of prostate cancer by analyzing blood samples from two large cohorts. Blood samples were collected in 1982 from 14,916 participants of the Physicians' Health Study, a randomized trial of aspirin and beta- carotene among U.S. male physicians aged 40-84 years. These baseline samples were collected from men free from myocardial infarction, stroke, and cancer (except nonmelanoma skin cancer), and were stored at -82oC. We also propose to collect and analyze blood samples from 11,000 healthy men aged 60-80 participating in the Health Professionals Follow-Up Study (HPFS), a large cohort study begun in 1986. A wealth of questionnaire information is available for both cohorts, particularly HPFS, in which detailed dietary assessments have been made. Both cohorts are followed closely for the occurrence of prostate cancer, documented by medical records. Using a nested case-control design, we plan to analyze specimens from men who were subsequently diagnosed with prostate cancer, along with a random sample who remained free of diagnosed prostate cancer, age-matched with a 1:2 case-control ratio. We will test four major hypotheses: Hormones - We plan to assay the specimens for levels of estradiol, free testosterone, dihydrotestosterone and prolactin. Fatty Acids - preliminary data from both cohorts suggest a higher risk of prostate cancer among men with high plasma levels of short chain saturated, trans-unsaturated, and alpha-linolenic fatty acids. We will assay plasma fatty acids in cholesteryl esters and red cell membranes. Antioxidants - We will assay the specimens for retinol, beta-carotene, other carotenoids (including lycopene, for which a protective effect is strongly suggested in preliminary data), and vitamin E. Iron - several studies, including our own preliminary data, suggest that high iron stores as reflected in plasma ferritin, as well as increased transferrin, may increase risk of incidence and progression of this cancer. Prostate- Specific Antigen (PSA) - An elevated PSA level is a relatively specific and sensitive marker for the presence of prostate cancer, but only sparse data are available on its lead time. by assaying samples collected in 1982 among men who subsequently were diagnosed (or not diagnosed) with prostate cancer over the ensuing 13 years, we can learn much about the natural history and potential use of this marker. Together, these cohorts will constitute the largest longitudinal questionnaire and blood- based study of prostate cancer; we are confident useful findings will emerge.